WO1985004329A1 - Lipoproteines marquees radio-activement et leur procede de preparation - Google Patents

Lipoproteines marquees radio-activement et leur procede de preparation Download PDF

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Publication number
WO1985004329A1
WO1985004329A1 PCT/US1985/000500 US8500500W WO8504329A1 WO 1985004329 A1 WO1985004329 A1 WO 1985004329A1 US 8500500 W US8500500 W US 8500500W WO 8504329 A1 WO8504329 A1 WO 8504329A1
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Prior art keywords
lipoprotein
technetium
dtpa
ldl
isotope
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PCT/US1985/000500
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English (en)
Inventor
Robert S. Lees
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Lees Robert S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Lees Robert S filed Critical Lees Robert S
Publication of WO1985004329A1 publication Critical patent/WO1985004329A1/fr
Priority to DK550385A priority Critical patent/DK550385D0/da

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A61K51/1224—Lipoprotein vesicles, e.g. HDL and LDL proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to biologically active lipoproteins labelled with radioisotopes especially suited for extracorporeal imaging, and more specifically to lipoproteins labelled with technetium isotopes and methods for making same.
  • lipoprotein metabolism has been monitored in vivo by introducing intravenously lipoproteins labelled with the radioisotope 125 l, and following the radioactivity with time in blood and/or urine. Since the isotope is a gamma emitter, the radiation image depicts the sites of metabolic activity and to some extent the degree thereof. Lipoprotein ' metabolism is of special interest because of its close association with atherosclerosis. For example, as set forth in United States Application serial number 425,187, filed September 18, 1982, atherosclerotic lesions take up
  • 125I-labelled low density lipoproteins can be monitored by extracorporeal gamma radiation imaging in animals and man after introduction of the lipoproteins in the bloodstream.
  • these measurements are somewhat limited by the poor imaging characteristics of 12 5 Ie
  • Isotopes such as Technetium-99m
  • coupling these isotopes to lipoproteins (and to biological molecules in general) may result in loss of native structure or biological function of the coupled molecules.
  • Lipoproteins are especially unstable in that they readily denature at pH 7 and below. This restricts the range of chemical procedures that can be used to couple radioisotopes to lipoproteins.
  • biological molecules also have "active sites" (parts of their molecules that are responsible for their biological interactions with other body chemicals or structural components) , and attachment of a radioisotope to these sites may interfere chemically or sterically with these interactions. Therefore, even when an isotope-coupled molecule is not denatured, it is not necessarily biologically active in the same way and to the same degree as its non-coupled counterparts. Such an isotope-coupled molecule would not suffice for studying a particular biological reaction of interest.
  • Technetium-99m(99 ⁇ i ⁇ C ) is an isotope especially l suited for external imaging.
  • 99Tc stable isotope
  • Jones et al Journal of Nuclear Medicine _2_L : 279-281, 1980
  • DePamphilis et al Inorganic Chemistry 22:2292-2297, 1983
  • a reducing agent effective in making this stable complex is sodium dithionite.
  • DTPA diethylene triamine pentaacetic acid
  • albumin albumin
  • IgG immunoglogulin G
  • Krejarek and Tucker couple DTPA to HSA utilizing a carboxycarbonic anhydride of DTPA.
  • the coupling procedure involves an initial reaction at pH 7-8, then dialysis against acetate buffer at pH 5.5, and subsequent isolation of the DTPA-HSA product by column chromatography at pH 3.5. Indium is added at pH 3.5 to chelate DTPA-HSA.
  • the pHs employed by Krejarek and Tucker would also denature lipoproteins.
  • Hnatowitch uses a cyclic anhydride of DTPA, which appears to be more reactive with some proteins than the carboxycarbonic anhydride of DTPA, and therefore can be coupled to these proteins with greater efficiency and under milder reaction conditions.
  • Optimal coupling occurs at pH 7 (again, a pH which may not be useable with lipoproteins).
  • both DTPA coupling procedures described above by Krejarek and Hnatowitch are not directly applicable to lipoproteins for subsequent chelation with a radioisotope.
  • Even slight changes in reaction conditions are known to affect the resulting product. For example, altering reaction conditions can lower the efficiency of DTPA coupling to protein, which reduces the amount of radiolabel that can be chelated to the DTPA-coupled protein.
  • the resulting product may have insufficient specific radioactivity for practical use.
  • the resulting product may not have the desired biological activity. Such changes in biological activity are even more likely to occur when larger compounds, such as DTPA, are coupled to the biomolecule.
  • the present invention aims to provide an improved radiolabelled lipoprotein, that is suitable for extracorporeal imaging.
  • Yet another object of the present invention is to provide a method for radiolabelling a lipoprotein or other molecule having biological activity exhibited by a lipoprotein with isotopes suitable for extracorporeal imaging.
  • the invention comprises biologically active lipoproteins, or other molecules having one or more of the biological functions of lipoproteins, which are radiolabelled with technetium (Tc) . More specifically. the invention comprises biologically active low density lipoproteins (LDL) radiolabelled with a technetium isotope, and methods for making such labelled lipoproteins.
  • a preferred method for preparing technetium-labelled low density lipoprotein complexes (Tc-LDL) is by simultaneous reduction of LDL and pertechnetate (Tc0 4 _ ) with sodium dithionite at pH 8-9.
  • Tc-LDL is separated from unreacted technetium and dithionite by either molecular sieve. chromatography, or by filtration.
  • the chelating agent, DTPA may be coupled to LDL, and the coupled DTPA-LDL product is then isolated.
  • a technetium isotope is subsequently chelated to the DTPA-LDL by reduction in the presence of sodium dithionite, and the radiolabelled Tc-DTPA-LDL complex is separated from uncomplexed technetium by molecular sieve chromatography.
  • FIG. 1A represents a chromatography column elution profile from a reaction mixture of LDL, Tc0 4 _ , and sodium dithionite, incubated according to the methods. Solid lines represent radioactivity and dotted lines protein.
  • FIG. IB represents a chromatography column elution profile from a reaction mixture of DTPA-LDL, TcO ⁇ -, and sodium dithionite, incubated according to the methods. Solid lines represent radioactivity and dotted lines protein.
  • FIG. 1C represents a chromatography column elution profile from mixtures of native LDL and Tc0 4 ⁇ , incubated according to the methods but with no sodium dithionite. Solid lines represent radioactivity and dotted lines protein.
  • FIG. 2A represents immunoelectrophoresis profiles of -5 native LDL and Tc-LDL.
  • FIG. 2B represents a subsequent autoradiograph of the immunoelectrophoresis profile of Tc-LDL.
  • TABLE 1 represents the biodistribution of 99m Tc-LDL in the rabbit 18 hr after intravenous injection of 4- 0 8 Ci of human 99m Tc-LDL.
  • Low density lipoproteins are isolated from normal ' human plasma, e.g. by sequential flotation using 5 equilibrium density centrifugation (Hatch and Lees,
  • the density of plasma is adjusted to 1.025 g/ml by addition of a potassium bromide solution, and ultracentrifuged for 22 hrs at 100,000g.
  • the supernatant (containing 0 lipoproteins having a density less than 1.025 g/ml) is removed and discarded.
  • the density of the infranatant is then adjusted to 1.050 g/ml by another addition of the potassium bromide solution and is ultracentrifuged for a second 22 hrs at 100,000g.
  • LDL 25 (containing low-density lipoproteins having a density between 1.025 to 1.050 g/ml) is removed and dialyzed for 24 hrs against a sodium bicarbonate buffer containing 0.15 M NaCl and 1.0 mM disodium EDTA, pH 8.6, or alternatively used without dialysis.
  • the LDL is filtered 0 through a 0.22 micron filter before use to remove any bacterial contamination.
  • LDL can be labelled directly with technetium (Tc), or indirectly through covalent attachment of a strong chelating group such as diethylenetriamine pentaacetic acid (DTPA), which is known to chelate a variety of metals including radioisotopes such as indium-Ill.
  • Tc technetium
  • DTPA diethylenetriamine pentaacetic acid
  • the radiolabelled LDL fraction is separated from denatured or aggregated LDL, uncoupled technetium, and sodium dithionite by molecular sieve chromatography.
  • the column is standardized with blue dextran and potassium iodide to determine the void volume and the column volume, respectively.
  • the reaction mixture is applied to the column and bicarbonate-EDTA buffer is used to elute column fractions.
  • the macromolecular radioactive peak that elutes at a position characteristic for LDL is isolated and is ready for use.
  • DTPA is coupled to lipoproteins by the following method as described by Krejarek and Tucker.
  • An aliquot of 5.5 - 25 ul (0.7 to.3.2 umoles) of a solution of a carboxycarbonic anhydride of DTPA is added to 2-3 ml of LDL (6 mg, 1.2 x 10 ⁇ 2 umoles) and the mixture is gently agitated.
  • the anhydride to protein molar ratio is as high as 300.
  • the pH is maintained j at 8 with 0.2 M NaHC0 3 .
  • the mixture is stirred for 15 minutes at room temperature and incubated at 4°C for 18 hrs. Unreacted DTPA is removed by dialysis against the bicarbonate-EDTA buffer.
  • the cyclic anhydride of DTPA is prepared by the method of Hnatowich et al, and is used to couple DTPA to lipoproteins by the following procedure.
  • Ten ug cyclic anhydride of DTPA is added to 3 mg of LDL in 1.0 ml 0.05 M sodium bicarbonate buffer at room temperature and the mixture is stirred for 10 minutes.
  • DTPA-coupled lipoprotein is separated from unreacted DTPA by passage over a Sephadex G25 chromatography column equilibrated with 0.2 M sodium bicarbonate buffer pH 8.
  • Technetium is then chelated to the DTPA-LDL by the procedure described above for direct labelling of native LDL.
  • Technetium in the form of Tc0 4 ⁇ , is added to the DTPA-LDL, and the mixture is reduced with sodium dithionite at pH 8-9.
  • Technetium-labelled DTPA-LDL is separated from uncomplexed technetium and sodium dithionite by column chromatography.
  • a technetium isotope with a long half life 9 Tc
  • 99m Tc which has a short half life.
  • the Tc isotope was used in experiments determining labelling conditions and comparing the physical and chemical properties of the radiolabelled LDL with native LDL, as well as in preliminary in vivo tests demonstrating the biological activity of radiolabelled-LDL.
  • 99 Tc isotope was coupled to LDL, the foregoing labelling methods were followed, except that one uCi 99 Tc was substituted for 50 mCi 99m Tc.
  • FIG. 1A depicts resulting elution profiles for the direct-labelling method, i.e. for production of Tc-LDL.
  • the profile 10A represents radioactivity measurements of column eluate.
  • the profile 12A represents protein assays of the eluate as determined by ultraviolet absorbance at 280 nanometers.
  • the profile 10A indicates that one third to one half of the radioactivity eluted in a macromolecular peak corresponding in position to native LDL. The remaining radioactivity eluted in a volume characteristic of small molecules.
  • FIG. IB depicts the elution profile for the indirect labelling method, i.e. for production of Tc-DTPA-LDL.
  • the profiles 10B and 12B which correspond with the profiles 10A and 12A, respectively, indicate essentially the same observations for Tc-DTPA-LDL as were recorded ' for Tc-LDL.
  • FIG. 1C depicts the resulting elution profiles for this mixture.
  • the profiles IOC and 12C which represent radioactivity measurements and protein assays, respectively, indicate that no radioactivity was detected in the native LDL peak.
  • radiolabelled LDL may be separated from the reaction components by filtration and washing, a procedure in which sterility is easier to maintain. 1
  • Tc-LDL and its reaction mixture were passed through a pre-sterilized 2 x 5 cm gel-filtration column of Sephadex G50M, as described above.
  • the elution profile was similar to that of native LDL, indicating negligible denaturation an -aggregation. Accordingly, a pH of 8-9 is preferred for producing technetium-labelled lipoproteins because it provides a relatively high labelling efficiency with minimal physical change in the LDL.
  • Tc-LDL obtained from the macromolecular chromatographic peaks and having a radioactivity of about 0.1 uCi was ultracentrifuged at a density of 1.063 g/ml for 22 hrs at 100,000g. The supernatant contained eighty-four percent of the total radioactivity (average of multiple samples). When experiments were repeated with Tc-DTPA-LDL, the supernatant contained seventy-nine percent of the total radioactivity after ultracentrifugation. No concentration of radioactivity was observed at the bottom of the tube.
  • LDL, 99 Tc-LDL, DTPA--LDL, and 99 Tc-DTPA-LDL demonstrated single bands with identical LDL mobility.
  • electrophoretic strips containing 99 Tc-LDL and 99 Tc-DTPA- LDL were scanned for radioactivity in a strip counter, a single peak of radioactivity was obtained, and these peals were located in the lipid-stained bands for these materials.
  • a control of reduced technetium also remained at the origin as indicated by a single sharp peak of radioactivity.
  • FIG. 2B represents an autoradiograph of the same immunoelectrophoresis slide shown in FIG. 2A.
  • the profile 16B represents the distribution of radioactivity present in Tc-LDL after immunoelectrophoresis.
  • Profile 16B shows a single arc, of uniform radioactivity, superimposing the immunoprecipitin arc 16A.
  • the immunoelectrophoresis and autoradiography results further indicate the similarity between Tc-LDL and native LDL with respect to mobility, homogeneity and immunologic identity. 4.
  • the stability of the technetium-LDL bond and the distribution of the label between protein and lipid were investigated by extraction with chloroform-methanol.
  • the lipid component of LDL solubilizes in the chloroform phase and the protein component of LDL remains in the aqueous phase.
  • Technetium that is loosely bound to LDL is also soluble in the aqueous phase.
  • Radiolabel bound to the protein can be separated from unbound radiolabel by precipitating the protein from the aqueous phase by addition of trichloroacetic acid.
  • Tc-LDL prepared by the method described above was mixed with chloroform-methanol 2:1 (v/v) . After vortexing and centrifugation, the chloroform layer was removed and the radioactivity was measured. Protein from the remaining aqueous layer was precipitated with trichloroacetic acid and the radioactivity in the precipitate was determined. The protein precipitate contained 78-90% of the total radioactivity, while chloroform-extracted lipids contained only 2.4-4.4% of the radioactivity.
  • Tc-LDL 99 Tc-LDL (0.15 uCi, 1.7 mg human LDL protein) prepared according to my methods and filtered through a 0.22 micron filter just prior to injection. Blood samples were collected at intervals over a 36 hour period post-injection. After each collection, plasma was separated at 40c and divided into aliquots for radioactivity measurements and for isolation of Tc-LDL by ultracentrifugation at a density of 1.063 g/ml.
  • Plasma clearance of human Tc-LDL from the rabbit was biexponential, the slower component had a half-life of 18-22 hours, similar to previous results obtained with ⁇ - 2 ⁇ I-LDL.
  • Blood samples that were drawn from 1 to 12 hours post injection and ultracentrifuged demonstrated 70-80% of the plasma radioactivity in the floating fraction which contained the LDL.
  • the biodistribution of " ⁇ » ⁇ c-LDL is expressed in percent of injected radioactivity per gram and per organ, as shown in Table 1.
  • the intensity of the image visualized for each organ was found to be proportional to the radioactivity measured in the biodistribution study.
  • LDL is known to bind to certain organs through a high affinity receptor, which involves the lysine and arginine residues of LDL.
  • a high affinity receptor which involves the lysine and arginine residues of LDL.
  • patients who have a congenital deficiency in, or total lack of, this high-affinity receptor are known to have early and severe atherosclerosis, with high concentrations of LDL in their arteries.
  • methylated Tc-LDL should be desirable for use as a probe for extracorporeal imaging of arteries because it still binds to arterial lesions while having a reduced affinity for binding sites in other organs.
  • i ' t will provide an arterial image with less uptake by other organs and thus less confusing background radioactivity.

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Abstract

Les lipoprotéines marquées radio-activement avec un isotope du technétium conservent leur structure native et leur fonction biologique. Les lipoprotéines peuvent être marquées radio-activement par réduction simultanée de pertechnétate et d'une lipoprotéine avec du dithionite de sodium à pH 8-9. Les lipoprotéines marquées radio-activement résultantes peuvent être utilisées comme sondes pour une représentation extra-corporelle afin d'analyser le métabolisme lipoprotéique.
PCT/US1985/000500 1984-03-28 1985-03-27 Lipoproteines marquees radio-activement et leur procede de preparation WO1985004329A1 (fr)

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DK550385A DK550385D0 (da) 1984-03-28 1985-11-28 Radioaktivt maerkede lipoproteiner og fremgangsmaade til fremstilling heraf

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US06/594,244 US4647445A (en) 1984-03-28 1984-03-28 Radiolabelled lipoproteins and method for making same
US594,244 1984-03-28

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264333A2 (fr) * 1986-10-17 1988-04-20 Cytogen Corporation Méthode de préparation de compositions de protéine, chélateur et ion métallique, convenant à l'injection
EP0413766A1 (fr) * 1988-05-02 1991-02-27 New England Deaconess Hospital Corporation Peptides synthetiques pour imagerie arterielle
US5726153A (en) * 1988-05-02 1998-03-10 New England Deaconess Hospital Corporation Synthetic peptides for arterial imaging
US5955055A (en) * 1988-05-02 1999-09-21 New England Deaconess Hospital Corporation Synthetic peptides for arterial imaging at vascular imaging sites
EP1718282A1 (fr) * 2004-01-15 2006-11-08 Mount Sinai School of Medicine Procedes et compositions con us pour l'imagerie

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US4937067A (en) * 1984-12-13 1990-06-26 Massachusetts Institute Of Technology Method and means for detection of adrenal metabolic activity
CA1285223C (fr) * 1986-11-10 1991-06-25 New England Deaconess Hospital Detection des affections vasculaires
US4877599A (en) * 1986-11-10 1989-10-31 New England Deaconess Hospital Corporation Detection of vascular disease with labelled antibodies
US5164175A (en) * 1986-12-10 1992-11-17 Hoechst Aktiengesellschaft Diagnostic aid containing an organ-specific substance labeled with technetium-99m
US4871836A (en) * 1987-10-13 1989-10-03 E. R. Squibb & Sons, Inc. Boronic acid adducts of rhenium and radioactive isotopes of rhenium dioxime complexes
US4917878A (en) * 1988-05-02 1990-04-17 Thomas Jefferson University Novel use of a radiolabelled antibody against stage specific embryonic antigen for the detection of occult abscesses in mammals
CA1340977C (fr) * 1988-11-15 2000-04-25 Monty Krieger Recepteur proteique capteur, ainsi que son anticorps
EP0486622B1 (fr) * 1989-08-09 1998-11-04 Rhomed, Incorporated Radiomarquage direct d'anticorps et d'autres proteines a l'aide de technetium ou de rhenium
US5078985A (en) * 1989-08-09 1992-01-07 Rhomed, Incorporated Radiolabeling antibodies and other proteins with technetium or rhenium by regulated reduction
AU5014793A (en) * 1992-08-28 1994-03-29 Magainin Pharmaceuticals, Inc. Purification of amphiphilic compounds
US6080384A (en) * 1997-03-25 2000-06-27 American Biogenetic Sciences, Inc. Methods for radionuclide-labeling of biomolecules and kits utilizing the same
US6764817B1 (en) 1999-04-20 2004-07-20 Target Discovery, Inc. Methods for conducting metabolic analyses
US6782289B1 (en) 1999-10-08 2004-08-24 The Board Of Trustees Of The Leland Stanford Junior University Methods and apparatus for characterizing lesions in blood vessels and other body lumens
US7328058B2 (en) 2000-01-04 2008-02-05 Gamma Medica-Ideas, Inc. Intravascular imaging detector
US20030152513A1 (en) * 2001-09-06 2003-08-14 Imetrix, Inc. Intravascular delivery of therapeutic and imaging agents to stressed and apoptotic cells using annexin V as a targeting vector
US7651506B2 (en) * 2003-10-02 2010-01-26 University Of Florida Research Foundation, Inc. Frameless stereotactic guidance of medical procedures
US7874975B2 (en) * 2005-07-20 2011-01-25 Clear Vascular, Inc. Methods and compositions for treating luminal inflammatory disease
US9623129B2 (en) * 2005-09-26 2017-04-18 Snip Holdings, Inc. Methods and therapies for treating inflammatory conditions with exposed collagen
US8361494B2 (en) * 2006-03-10 2013-01-29 The Trustees Of The University Of Pennsylvania Biomimetic iron-oxide-containing lipoprotein and related materials
EP3913367A1 (fr) 2008-12-30 2021-11-24 Children's Medical Center Corporation Procédé de prédiction d'une appendicite aiguë

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US4293537A (en) * 1978-09-05 1981-10-06 Wong Dennis W Novel chemical method of labeling proteins with 99m Tc-Technetium at physiological condition
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US4364920A (en) * 1975-04-30 1982-12-21 Medi-Physics, Inc. Stable diagnostic reagents
US4057617A (en) * 1975-05-15 1977-11-08 Abramovici J Method of labeling proteins with technetium
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264333A2 (fr) * 1986-10-17 1988-04-20 Cytogen Corporation Méthode de préparation de compositions de protéine, chélateur et ion métallique, convenant à l'injection
EP0264333A3 (fr) * 1986-10-17 1988-07-06 Cytogen Corporation Méthode de préparation de compositions de protéine, chélateur et ion métallique, convenant à l'injection
EP0413766A1 (fr) * 1988-05-02 1991-02-27 New England Deaconess Hospital Corporation Peptides synthetiques pour imagerie arterielle
US5726153A (en) * 1988-05-02 1998-03-10 New England Deaconess Hospital Corporation Synthetic peptides for arterial imaging
US5955055A (en) * 1988-05-02 1999-09-21 New England Deaconess Hospital Corporation Synthetic peptides for arterial imaging at vascular imaging sites
EP1718282A1 (fr) * 2004-01-15 2006-11-08 Mount Sinai School of Medicine Procedes et compositions con us pour l'imagerie
EP1718282A4 (fr) * 2004-01-15 2010-07-14 Sinai School Medicine Procedes et compositions con us pour l'imagerie
US7947307B2 (en) 2004-01-15 2011-05-24 Mount Sinai School Of Medicine Of New York University Methods and compositions for imaging
US8097283B2 (en) 2004-01-15 2012-01-17 Mount Sinai School Of Medicine Methods and compositions for imaging

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GR850788B (fr) 1985-11-25
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US4647445A (en) 1987-03-03
CA1249513A (fr) 1989-01-31
EP0176562A1 (fr) 1986-04-09

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